Clinical Research in Cardiology

Chronic low-grade systemic inflammation is a key component in atherogenesis. Decreased heart rate variability (HRV), a strong predictor of cardiovascular events, has been associated with elevations in circulating levels of C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen in apparently healthy individuals. We investigated whether decreased HRV is associated with inflammatory markers in patients with coronary heart disease (CHD). We studied the relationship between HRV and CRP, IL-6, and fibrinogen in 862 outpatients with CHD. All participants provided fasting blood samples and underwent 24-h ambulatory monitoring to assess time-domain measures of HRV (MeanNN, SDNN, SDANN, and RMSSD). Regression analyses were adjusted for age, sex, ethnicity, body mass index, smoking, diabetes, beta blocker use, and cardiopulmonary history. MeanNN, SDNN, and SDANN were significantly and inversely associated with CRP and IL-6 levels in age-adjusted models and after adjustment for all covariates (p ≤ 0.02). MeanNN, SDNN, and SDANN were also inversely associated with fibrinogen levels in age-adjusted models (p < 0.03), but not significantly so in multivariable-adjusted models. Reduced vagal modulation of heart rate (RMSSD) was not significantly associated with any inflammatory measures. Reduced cardiac autonomic control is associated with increased systemic inflammation in patients with stable CHD. This relationship was largely independent of important covariates.

Patients with diabetes who had a recent myocardial infarction (MI) are at high risk of cardiovascular events. Therefore, risk assessment is important for treatment and shared decisions. We used data from EXAMINE trial to investigate whether a multi-proteomic approach would provide specific proteomic signatures and also improve the prognostic capacity for determining the risk of cardiovascular death, MI, stroke, heart failure [HF], all-cause death, and combinations of these outcomes. 93 circulating proteins (92 from the Olink® CVDII plus troponin) were assessed in 5131 patients. Cox, competing risks, and reclassification measures were applied. The clinical model showed good discrimination and calibration for all outcomes. On top of the clinical model that included age, sex, smoking, diabetes duration, history of MI (prior to the index MI of inclusion), history of HF hospitalization, history of stroke, atrial fibrillation, hypertension, systolic blood pressure, statin therapy, estimated glomerular filtration rate, and study treatment (alogliptin or placebo), troponin and BNP added prognostic information to the composite of cardiovascular death, MI, or stroke (∆C-index + 5%) and cardiovascular death alone (∆C-index + 7%). Troponin, BNP, and TRAILR2 added prognostic information on all-cause death and the composite of cardiovascular death or HF hospitalization. HF hospitalization alone was improved by adding BNP and Gal-9. For MI, troponin, FGF23, and AMBP added prognostic value; whereas for stroke, only troponin added prognostic value (multi-proteomics improved C-index > 3% [p < 0.001] for all the studied outcomes). The addition of the final biomarker selection to the clinical model improved event reclassification (cNRI from + 23% to + 64%). Specifically, the addition of the biomarkers allowed a better classification of patients at low risk (as having “true” low risk) and patients and high risk (as having “true” high risk). These results were consistent for all the studied outcomes with even more marked differences in the fatal events. The addition of multi-proteomic biomarkers to a clinical model in this population with diabetes and a recent MI allowed a better risk prediction and event reclassification, potentially helping for better risk assessment and targeted treatment decisions. T2D type 2 diabetes, MI myocardial infarction, CV cardiovascular, HFH heart failure hospitalization, Δ delta, cNRI continuous net reclassification index, BNP brain natriuretic peptide, TRAILR2 trail receptor 2 (or death receptor 5), Gal-9 galectin-9, FGF23 fibroblast growth factor 23.

Electromyostimulation (EMS) of thigh and gluteal muscles is a strategy to increase exercise capacity in patients with chronic heart failure (CHF). The aim of this non-randomised pilot study was to investigate the effects of different stimulation strategies in CHF patients using a newly developed stimulation suit also involving trunk and arm muscles [extended electromyostimulation (exEMS)] in comparison with EMS therapy limited to gluteal and leg muscles (limEMS). 60 individuals joined the EMS training programme. Stable CHF patients (NYHA class II–III) received either exEMS (22 patients, 15 males, mean age 59.95 ± 13.16 years) or limEMS (12 patients, 9 males, 62.75 ± 8.77 years). 26 participants served as healthy control group (CG) receiving exEMS. Training was performed for 10 weeks twice weekly for 20 min, and the level of daily activity remained unchanged. Effects on exercise capacity, oxygen uptake, left ventricular function (EF) and biomarkers were evaluated. There was a significant increase of oxygen uptake at aerobic threshold in all groups (exEMS: 13.7 ± 3.9–17.6 ± 5.1 ml/kg/min (+28.46 %, p < 0.001); limEMS 13.6 ± 3.0–16.0 ± 3.8 ml/kg/min (+17.6 %, p = 0.003); CG 15.0 ± 4.9–17.0 ± 6.4 ml/kg/min (+13.3 %, p = 0.005). LVEF increased from 38.3 ± 8.4 to 43.4 ± 8.8 % (+13.3 %, p = 0.001) (limEMS 37.1 ± 3.0–39.5 ± 5.3 % (+6.5 %, p = 0.27); CG 53.9 ± 6.7–53.7 ± 3.9 % (−0.4 %, p = 0.18). In CHF patients changes in oxygen consumption and LVEF were higher in the exEMS group than in limEMS (not significant). Maximal workload improved in healthy controls (p = 0.002) but not in CHF patients. Extended EMS can improve oxygen uptake and EF in CHF. In patients with limited EMS and in control patients without heart failure but extended EMS, oxygen uptake can be improved but EF is unaltered. For all groups, NT proBNP is unaffected by EMS.

Bicuspid aortic valve may be associated with increased complications during transcatheter aortic valve implantation (TAVI). Compare balloon-expandable transcatheter heart valve (THV) safety and efficacy in severe tricuspid (TAV) and bicuspid (BAV) aortic stenosis. Transfemoral TAVI was performed in 743 patients (Jan 2014–June 2019) using the SAPIEN 3 THV. Aortic valve morphology was determined using computed tomography. Valve Academic Research Consortium-2 (VARC-2) derived safety and efficacy endpoints at 1 year were evaluated. BAV patients (n = 78), were younger (77 [72, 81] vs. 81 [78, 85] years, p < 0.001) with lower surgical risk (EuroSCORE II 2.96% vs. 4.51% p < 0.001). Bicuspid valves were more calcified (BAV 1308mm3, TAV 848mm3 p < 0.001) with more asymmetric calcification (BAV 63/78 (81%), TAV 239/665 (36%), p < 0.001). Device success (BAV 94%, TAV 90%, p = 0.45) and major vascular complications (BAV 6%, TAV 9%, p = 0.66) were comparable. At 1 year, there was a trend toward lower combined all-cause mortality and rehospitalization for congestive heart failure in BAV patients (BAV 7%, TAV 13%, p = 0.08) with significantly lower all-cause mortality in this cohort (BAV 1%, TAV 9%, p = 0.020). VARC-2 time-related valve safety (BAV 22%, TAV 20%, p = 0.60) was comparable; however, bioprosthetic valve thrombosis remained more common in BAV patients (BAV 7%, TAV 2%, p = 0.010, Hazard ratio 3.57 [95% confidence interval 1.26, 10.10]). After propensity score matching, only bioprosthetic valve thrombosis remained significantly different. Safety and efficacy of the SAPIEN 3 balloon-expandable THV in BAV is comparable with TAV. Higher rates of bioprosthetic valve thrombosis require further investigation.

Chronic kidney disease (CKD) adversely affects outcomes in patients with coronary artery disease. Data on the impact of renal impairment on prognosis of patients undergoing percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) are scarce. A total of 2002 patients undergoing CTO PCI were stratified according to baseline renal function (group 1: estimated glomerular filtration rate [eGFR] ≥ 90 ml/min/1.73 m2, group 2: 60 to 89 ml/min/1.73 m2, group 3: 30 to 59 ml/min/1.73 m2, and group 4: <30 ml/min/1.73 m2). The primary outcome measure was all-cause mortality at a median follow-up of 2.6 (interquartile range 1.1–3.1) years. All-cause mortality increased with decreasing renal function (group 1: 5.0%, group 2: 9.5%, group 3: 26.4%, and group 4: 38.7%, log rank p < 0.001). Continuous eGFR values were significantly related with all-cause mortality (adjusted HR 0.98, 95% CI 0.98–0.99, p < 0.001). Procedural failure was associated with all-cause mortality both in patients with an eGFR < 60 ml/min/1.73 m2 (42.6 vs. 23.7%, adjusted HR 1.59, 95% CI 1.08–2.32, p = 0.02) and in those with an eGFR ≥ 60 ml/min/1.73 m2 (14.6 vs. 6.5%, adjusted HR 1.73, 95% CI 1.15–2.60, p = 0.009, interaction p = 0.47). Although renal impairment is associated with all-cause mortality in patients undergoing CTO PCI, successful CTO recanalization is related to improved survival irrespective of renal function.

Prasugrel is a potent thienopyridine that may be preferentially used in younger patients with lower bleeding risk. We compared prasugrel use and outcomes by age from the PROMETHEUS study. We also assessed age-related trends in treatment effects with prasugrel versus clopidogrel. PROMETHEUS was a multicenter acute coronary syndrome (ACS) percutaneous coronary intervention (PCI) registry. We compared patients in age tertiles (T1 < 60 years, T2 60–70 years, T3 > 70 years). Major adverse cardiac events (MACE) were a composite of death, myocardial infarction, stroke or unplanned revascularization. Data were adjusted using multivariable Cox regression for age-related risks and propensity score stratification for thienopyridine effects. The study included 19,914 patients: 7045 (35.0%) in T1, 6489 (33.0%) in T2 and 6380 (32.0%) in T3. Prasugrel use decreased from T1 to T3 (29.2% vs. 23.5% vs. 7.5%, p < 0.001). Crude 1-year MACE rates were highest in T3 (17.4% vs. 16.8% vs. 22.7%, p < 0.001), but adjusted risk was similar between the groups (p-trend 0.52). Conversely, crude incidence (2.8% vs. 3.8% vs. 6.9%, p < 0.001) and adjusted bleeding risk were highest in T3 (HR 1.24, 95% CI 0.99–1.55 in T2; HR 1.83, 95% CI 1.46–2.30 in T3; p-trend < 0.001; reference = T1). Treatment effects with prasugrel versus clopidogrel did not demonstrate age-related trends for MACE (p-trend = 0.91) or bleeding (p-trend = 0.28). Age is a strong determinant of clinical risk as well as prasugrel prescription in ACS PCI with much lower use among older patients. Prasugrel did not have a differential treatment effect by age for MACE or bleeding. Frequency of prasugrel use and age-related temporal risks of all-cause death and bleeding after ACS PCI.